Arteriosclerosis is a major source of adult morbidity and mortality in industrialized countries. The condition may lead to a number of complications, including coronary thrombosis, myocardial ischemia, unstable angina, myocardial infarction and restenosis of stents and bypass grafts. The classification of atherosclerotic lesions by type can be valuable in predicting clinical complications, and the type of plaque is likely a better predictor of cardiovascular events than angiographic data.
Unstable plaque is well established as producing high risk for sudden myocardial infarction, either through plaque rupture and subsequent thrombotic response, or thrombosis generated at the inflamed surface of the plaque. The rupture of unstable plaque, and the subsequent generation of thrombus, has been estimated to account for 60 to 70 percent of fatal myocardial infarctions and up to 85 percent of all myocardial infarctions.
Unstable plaque is characterized by a lipid-rich core, chronic inflammation, thin fibrous cap, and activated macrophages. Angiography can identify the presence of a ruptured plaque after rupture, but not before rupture. Thus, it cannot determine the risk associated with a given plaque.
Due to chronic inflammation, the temperature of unstable plaque is typically elevated above that of the adjacent sites on the inner lumen of the vessel. Extensive research has been conducted to confirm the elevated temperatures of unstable plaques, and to develop techniques to clinically identify them. It has been found that there is a correlation between the temperature of atherosclerotic plaque and the vulnerability to blood vessel rupture. In particular, it has been determined that inflamed, unstable deposits typically give off more heat than do healthy, non-inflamed tissues. Accordingly, there have been various apparatus and methods proposed to monitor the temperature of the vessel wall without occluding blood flow. U.S. Pat. Nos. 5,871,449; 5,924,997; and 5,935,075 provide background with regard to the general approach.
To determine that thrombotic events could be predicted through thermal measurements on the plaque surface, Willerson et al. measured the intimal surface temperatures on 20 sites located on 50 samples of excised living carotid artery samples from 48 patients using a thermistor, and then conducted histological studies. The results showed 37% of plaque regions warmer by up to 2.2° C. These warmer regions could not be distinguished from cooler regions by visual observation, but correlated positively with cell density, a marker of inflammation.
Stefanadis et al. conducted human in vivo measurements of plaques using a Betatherm Microchip NTC 100K6 MCD368, 0.457 mm diameter thermistor on the end of a guide wire pressed against the vessel wall by a hydrofoil. They measured thermal heterogeneity of plaque temperatures repeatedly with an accuracy of 0.05° C. and spatial and temporal resolutions of 500 um and 300 ms, in 90 patients with normal coronary arteries, stable angina, unstable angina, and with acute myocardial infarction. This group found artery-wall temperatures that increased progressively from normal patients, to stable angina patients, to unstable angina patients. The measurement of temperature differences in the inner lumen of coronary arteries shows great promise for identifying sites of unstable plaque.
Research on classification of plaque as stable or unstable has been carried out in three main areas: thermal, Ultra-Fast Magnetic Resonance Imaging (MRI) and Intravascular Ultrasound (IVUS), with some work on a few others (e.g. Raman scattering, elastography, optical coherence tomography). While MRI and IVUS show promise, only thermal techniques offer a direct, inexpensive method of plaque classification that, due to its minimal hardware and disposable requirements, can be quickly and inexpensively implemented.
Plaque classification by MRI presents numerous obstacles. It brings the problems of requiring a special machine, typically located in other regions of the facility and not available on an ad hoc basis, into the cath lab as questions of plaque stability may arise. The ability of MRI to characterize human atherosclerotic plaque has been investigated by comparing MRI images of carotid artery plaque with histologic examination of the specimens after carotid endarterectomy. The studies indicated that MRI can discriminate the presence of a lipid core and fibrous cap in the carotid artery. The ability of MRI to characterize plaque composition of coronary arteries in the beating human heart has not been demonstrated. Even if the technical challenges of spatial and temporal resolution are solved, the cost of imaging coronary arteries using MRI is likely to be substantial.
While IVUS can accurately identify arteriosclerosis in its early stages, it is much less effective in the classification of plaque by type. Further, IVUS requires expensive and large equipment that also must be brought into the cath lab when needed. The main limitation of IVUS is cost. IVUS enjoys an installed base in many cath labs, unlike other competing technologies to classify plaque, but it is problematic in this application. IVUS is very operator dependent and typically has a 300 micron resolution, the thickness of the fibrous cap on unstable plaque. Thus, IVUS does not have the needed resolution to identify unstable plaque. Although numerous clinical studies have been performed with IVUS, there are very limited follow-up data to suggest that IVUS examination of a coronary artery can be used to predict the probability that a plaque will rupture.
Yamagishi et al. performed IVUS examination of 114 coronary plaques in 106 patients. During an average follow-up period of 22 months, 12 patients had an acute coronary event related to a plaque that was previously examined by IVUS. Ten of the 12 plaques contained an echolucent zone consistent with a lipid-rich core. Only 4 of 90 sites not associated with acute events had an echolucent zone (p<0.05).
Optical Coherence Tomography (OCT) has problems due to its limited penetration distance, and the fact that it requires a saline flush to remove blood from the area and permit transmission of the optical radiation. Further, it can run only at ˜5 frames/sec., which does not provide adequate temporal resolution. This technique, and others, such as pulsed laser radiation and the use of Raman scattering spectroscopy, require the vessel be purged of blood with clear saline for the signals to propagate. Further, they are much less developed than other techniques.
Classification of atherosclerotic plaque stability by measurement of its surface temperature is direct. Due to the chronic inflammation, the surface temperature of unstable plaque is typically elevated above that of the adjacent sites on the inner lumen of the vessel. Measurements in vivo and ex vivo have been made of active plaque sites, with temperature differences from the adjacent normal artery wall ranging up to 2 to 3° C. The equipment associated with thermal measurements may be small and inexpensive, thus easily portable between cath labs or available in all cath labs in a single facility, as opposed to Magnetic Resonance Imaging (MRI) and Intravascular Ultrasound (IVUS). Identification of unstable plaques would permit the cardiologist to decide on treatment on a site-by-site basis during a single catheter insertion.
There are numerous potential treatments for these unstable lesions, including anti-inflammatory and/or anti-microbial treatments, aggressive cholesterol lowering, and heating to generate apoptosis. Stenting techniques are influenced by the classification of the plaque being treated. As classification of plaques becomes established, other therapeutic techniques will no doubt develop.
While plaque temperature measurement and catheters therefore showed early promise in terms of early diagnosis and treatment, it has more recently been discovered that the temperature elevation to be identified as representative of unstable lesions is complicated by the “cooling affect” of blood flow. In particular, a recent paper by Stefanadis, entitled Thermal Heterogeneity in Stable Human Coronary Atheroschlerotic Plaques is Underestimated in Vivo: The “Cooling Effect” of Blood Flow postulates that the “cooling effect” of blood flow may lead to an underestimation of in vivo temperature measurements associated with atheroschlerotic plaques.
Accordingly, the need remains for an improved system and method for analyzing plaque tissues exhibiting an elevated temperature, both to predict rupture or other clinical events.